The competing renewal of this Program Project grant (PPG) builds on important research conducted during the last 10 years in the development of in vitro and in vivo models of Alzheimer's Disease (AD) amyloidosis for the purpose of elucidating mechanisms leading to the regulation of amyloid beta (Abeta) pathogenesis. These studies are sharply focused on addressing a novel hypothesis that emerged from studies conducted in the previous funding cycle of this PPG to account for the neurotoxicity of Abeta. A "two hit" hypothesis is proposed which states that the "first hit" (i.e., elevation of full length Abeta) is necessary but not sufficient to induce neurodegeneration, and that a "second hit" (i.e. genetic and epigenetic factors) is required to render neurons susceptible to the toxic effects of Abeta. In addition to being plausible and compatible with our own preliminary data and the published literature on the biological effects of Abeta in vitro and in vivo, this hypothesis can be rigorously tested by accomplishing the goals of Projects 1-4 in this PPG application where so-called "second hit" events that augment Abeta toxicity could be oxidative stress, lipid peroxidation, traumatic brain injury, the involvement of other Abeta fragments in senile plaque formation, neurofibrillary tangles, Lewy bodies or other processes identified to occur in the AD brain. To test this hypothesis, the investigators use complementary research strategies to pursue four separate projects: 1) Cell Biology of Abeta Production (RW Doms); 2) Novel Abeta Fragments as Mediators of Alzheimer's Disease (V. M.-Y. Lee); 3) Lipid peroxidation and Alzheimer's disease phenotypes (D. Pratico); and 4) Traumatic Brain Injury and Alzheimer's Disease (J. Q. Trojanowski). With the support of the Administrative and Neuroscience Cores, the investigators will use a multi-disciplinary approach to work synergistically to advance understanding of mechanisms of Abeta-mediated neuron degeneration in AD at the molecular, cellular and in vivo levels. It is anticipated that information derived from this research could provide a rationale for the development of novel therapeutic interventions for AD.